1. Field of the Invention
The present invention provides methods of treatment and prevention of selectin-dependent acute lung injury and diseases which result from selectin-dependent acute lung injury by administration of a sulfatide. The present invention also provides pharmaceutical compositions for the treatment and prevention of inflammatory lung injury and diseases which selectin-dependent.
2. Discussion of the Background
Acute lung injury develops following systemic activation and intrapulmonary deposition of IgG immune complexes in rats. Previously, acute lung injury has been treated in in vivo models with the use of antibodies (M. S. Mulligan et al, J. Immunol., In press (1994); M. S. Mulligan et al., J. Clin. Invest. 90, 1600 (1992)), selectin-Ig chimeras (M. S. Mulligan et al., J. Immunol. 151, 1 (1993)), synthetic fucosylated sialylated oligosaccharides (M. S. Mulligan et al., Nature 364, 149 (1993); M. S. Mulligan, et al., J. Exp. Med., 178, 623 (1993)) and a mixture of IL-4 and IL-10 (M. S. Mulligan et al., J. Immunol. 151, 5666 (1993)).
Selectins (L-, E- and P-) are lectin binding molecules that facilitate adhesive interactions between endothelial cells and leukocytes. This adhesion-promoting process causes the "rolling" phenomenon of leukocytes along endothelial surfaces and represents the first step in events that ultimately lead to leukocyte transmigration (reviewed, J. C. Paulson, in Adhesion: Its Role in Inflammatory Disease, J. M. Harlan, and D. Y. Lui, Eds. (W. H. Freeman and Co., New York, 1991). Current approaches for the in vivo blocking of selectin-dependent inflammatory reactions featuring the recruitment of neutrophils rely on the use of blocking antibodies to selectins (M. A. Jutila et al, J. Immunol., 143, 3318 (1989); M. S. Mulligan et al, J. Immunol., 152, 832 (1994)), sialyl Lewis.sup.x (a fucosylated and sialylated oligosaccharide known to bind to selectins) (M. S. Mulligan et al., Nature 364, 149 (1993); M. S. Mulligan, et al., J. Exp. Med., 178, 623 (1993)), or the use of selectin-Ig chimeric proteins (S. R. Watson et al., Nature 349, 164 (1991); M. S. Mulligan et al., J. Immunol. 151, 1 (1993)).
Besides the family of oligosaccharides that are reactive with lectin binding sites on selectins, additional ligands are also known. These include sulfated glycolipids (such as sulfatides and seminolipids) (Y. Suzuki, et al., Biochem. Biophys. Res. Comm. 190, 426 (1993)), a sulfated and sialylated mucin-like molecule which is present in high venular endothelial cells of lymph nodes and has been termed Gly-CAM-1 (L. A. Laskey et al., Science 361, 555 (1993); L. A. Laskey et al., Cell 69, 927 (1991)), a sulfated heparin-like molecule extracted from endothelial cells (K. E. Nogard-Sumnicht, et al., Science 261, 480 (1993)), sulfated glycans (fucoidin, dextran sulfate) (L. M. Stoolman, et al., Cell. Biol. 99, 1535 (1984); T. A. Yednock, et al., J. Cell. Biol. 104, 713 (1987)), a sulfoglucuronyl glucosphingolipid (Needham and Schnaar, Proc. Nat'l. Acad. Sci. USA, 90, I355 (1993)), CD34 sialomucin (S. Baumhueter et al., Science 262, 436 (1993)), and sulfated oligosaccharides (such as sialyl Lewis.sup.x and sialyl Lewis.sup.a) (C-T. Yuen et al., Biochem. 31 9126 (1992)). Most of these lectins are reactive with L-selectin, while binding to P- and E-selectin has been variously reported (G. Todderud et al., J. Leukoc. Biol. 52, 85 (1992)). Virtually nothing is known regarding the in vivo blocking activity of these compounds in acute inflammatory reactions.
There remains a need for new methods which block events leading to inflammatory lung injury and the diseases which result in inflammatory lung injury.